Of great importance to man is the control of pathological cellular proliferation such as that which occurs in the case of cancer. Considerable research and resources have been devoted to oncology and antitumor measures including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling the growth of, for example, tumors, new methods and antiproliferative chemical compositions are needed.
In searching for new biologically active compounds, it has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activity of great diversity. For example, the diterpene commonly known as Taxol, isolated from several species of yew trees, is a mitotic spindle poison that stabilizes microtubules and inhibits their depolymerization to free tubulin (Fuchs, D. A., R. K. Johnson [1978] Cancer Treat. Rep. 62:1219-1222; Schiff, P. B., J. Fant, S. B. Horwitz [1979] Nature (London) 22:665-667). Taxol is also known to have antitumor activity and has undergone a number of clinical trials which have shown it to be effective in the treatment of a wide range of cancers (Rowinski, E. K. R. C. Donehower [1995] N. Engl. J. Med 332:1004-1014). See also, e.g., U.S. Pat. Nos. 5,157,049; 4,960,790; and 4,206,221.
Marine sponges have also proven to be a source of biologically active chemical molecules. A number of publications disclose organic compounds derived from marine sponges including Scheuer, P. J. (ed.) Marine Natural Products, Chemical and Biological Perspectives, Academic Press, New York, 1978-1983, Vol. I-V; Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y. Okumura, Y. Hirata [1985] J. Am. Chem. Soc. 107:4796-4798; Minale, L. et al. [1976] Fortschr. Chem. Org. Naturst. 33:1-72; Faulkner, D. J. [2001] Natural Products Reports 18:1-49; Gunasekera, S. P., M. Gunasekera, R. E. Longley and G. K. Schulte [1990] xe2x80x9cDiscodermolide: A new bioactive polyhydroxy lactone from the marine sponge Discodermia dissolutaxe2x80x9d J. Org. Chem., 55:4912-4915; [1991] J. Org. Chem. 56:1346; Hung, Deborah T., Jenne B. Nerenberg, Stuart Schreiber [1994] xe2x80x9cDistinct binding and cellular properties of synthetic (+)- and (xe2x88x92) discodermolidesxe2x80x9d Chemistry and Biology 1:67-71; Hung, Deborah T., Jie Cheng, Stuart Schreiber [1996] (+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks Taxol binding and results in mitotic arrestxe2x80x9d Chemistry and Biology 3:287-293. U.S. Pat. No. 4,801,606 and 4,808,590 (T. Higa, S. Sakemi and S. Cross) disclose related onnamide compounds, having antiviral, antitumor, and antifungal properties, isolated from the marine sponge Theonella sp.
Mycalamides A and B have been isolated from a New Zealand sponge Mycale sp. See, Mycalamide A, an antiviral compound from a New Zealand sponge of the genus Mycale. N. B. Perry, J. W. Blunt, M. H. G. Munro and L. K. Pannell. J. Amer. Chem. Soc., [1988] 110, 4850-4851 and Mycalamide compounds, compositions, thereof and methods of preparation and use, U.S. Pat. No. 4,868,204, J. W. Blunt, M. H. G. Munro, N. B. Perry, A. M. Thompson. Pederin, a related compound was isolated from a blister beetle Paederus fuscipes. Onnamide A was first isolated from an Okinawan sponge of the genus Theonella. Subsequently, a University of Tokyo group reported the isolation of related metabolites, viz. 13-des-O-methylonnamide A, dihydroonnamide A, onnamides B, C, D and E, and 17-oxo-onnamide B from the Hachijo-jima Island sponge Theonella swinhoei and pseudoonnamide A from a morphologically different sponge of the genus Theonella. (see, Isolation and structure elucidation of onnamide A, a new bioactive metabolite of a marine sponge, Theonella sp., S. Sakemi, T. Ichiba, S. Kohmoto, G. Saucy and T. Higa, J. Am. Chem. Soc., [1988] 110, 4851-4853; Antitumor activity and mechanism action of the novel marine natural products mycalamides A and B and onnamides. N. S. Burres and J. J. Clement, Cancer Research [1989] 49, 2935-2940; S. Matsunaga, N. Fusetani and Y. Nakao, Tetrahedron [1992] 48, 8369; and T. Matsumoto, M. Yanagiya, S. Maeno, S. Yasuda, Tetrahedron Lett., [1968] 6297). In 1992, Fusetani et al., reported related compounds, theopederins A-E also isolated from the sponge, Theonella sp. (J. Org Chem, [1992] 57, 3828-3832). Recently in 1999, the same group reported theopederins F-J. also isolated from the sponge, Theonella swinhoei (Tetrahedron [1999] 55, 13697-13702). The discalamides are structurally related to the theopederins but not identical to any known theopederins. Discalamide A has an extra double bond and a methoxy group as compared to theopederin G. Similarly, discalamide B has an extra double bond as compared to theopederin G. Therefore, discodermolides A and B are trivially named theopederins K and L, respectively.
A principal object of the subject invention is the provision of novel compositions of biologically active compounds. These compounds have been found to have potent antiproliferative activity. Because of this antiproliferative activity, the compounds of the subject invention can advantageously be used for immunomodulation and/or treating cancer.
Specifically exemplified herein are discalamides A and B and various analogs and derivatives of these compounds. Advantageously, these compounds possess potent activity against P388 and A459 tumor cells. These activities are at least the equivalent of, and at times surpass, the cytotoxic properties of such marine compounds as onnamide A, mycalamides A and B, lasonolide A, discodermolide and the ecteinascidins (729 and 743).
The compounds of the subject invention can be isolated from the sponge, Discodermia sp. Synthetic schemes have been worked out for many of this class of compounds, and such methodologies can be applied to the synthesis of discalamides A and B, and to various analogs and derivatives thereof (C. Y. Hong and Y. Kishi, J. Org. Chem. [1990] 55, 4242; C. Y. Hong and Y. Kishi, J. Am. Chem. Soc. [1991] 113, 9693).
In a specific embodiment, the novel compositions and methods of the subject invention can be used in the treatment of an animal hosting cancer cells including, for example, inhibiting the growth of tumor cells in a mammalian host. More particularly, the subject compounds can be used for inhibiting in a human the growth of tumor cells, including cells of breast, colon, CNS, ovarian, renal, prostate, bone, gastrointestinal, stomach, testicular, or lung tumors, as well as human leukemia or melanoma cells.
In accordance with the subject invention, methods for inhibiting tumors in a host include contacting tumor cells with an effective amount of the new pharmaceutical compositions of the invention. The tumor cells inhibited by the invention are those which are susceptible to the subject compounds described herein or compositions comprising those compounds. Additional aspects of the invention include the provision of methods for producing the new compounds and compositions.
Other objects and further scope of applicability of the present invention will become apparent from the detailed descriptions given herein; it should be understood, however, that the detailed descriptions, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent from such descriptions.